Method for producing 2-deoxy-L-ribose

ABSTRACT

The present invention relates to an economic synthetic method of 2-deoxy-L-ribose with easy reaction, separation and purification. The present invention consists of four (4) steps including protection, activation of 3- and 4-OH groups, inversion and deprotection steps. In respect to the cost for equipment, reagent and operation, by the present invention, 2-deoxy-L-ribose can be produced more economically because the invention uses 2-deoxy-L-ribose which is abundant in nature and easily synthesized from D-glucose and adopt simple and yielding process.

TECHNICAL FIELD

The present invention relates to a synthetic method for the compoundhaving compound (1) below, more specifically, to a mass-produceable andcost-effective synthetic method of compound (1) from 2-Deoxy-D-ribosewith easy reaction, separation, and purification.

BACKGROUND ART

Recently, natural or modified L-nucleoside are attracting attention asantiviral agents. Some L-nucleosides such as L-thymidine,L-2′-thiacytidine (3TC) and L-2′,3′-dideoxycytidine (L-ddC) are muchless toxic and have better antiviral activity than their D-isomers. Inaddition, L-nucleosides have good effect in antisense oligonucleotidetherapy.

For the above reasons, many attempts have been made to synthesizeL-nucleosides effectively which cannot be obtained as natural products.The efforts has been being focused to economic and mass-produceablepreparation method for the derivatives of L-sugar, particularly,2-deoxy-D-ribose and L-ribose which can be used as key intermediates ofL-nucleosides.

Some synthetic methods for 2-deoxy-L-ribose are known from D-ribose,L-arabinose or L-ascorbic acid. (WO 9839347, CS 274394B1, NucleosidesNucleotidees 1999, 18 (11 & 12), 2357-2365, Tetrahedron: Asymmetry 2000,11, 1869-176, Org. Lett 1999, 1 (10), 1517-1519).

In these methods, however, expensive or highly toxic reagents are used;difficult separation and purification is required; the overall yield islow; all which are obstacles to the application in the large-scalesynthesis.

DISCLOSURE OF INVENTION

Accordingly, the objective of the present invention is to provide asynthetic process of 2-deoxy-L-robse, which allows the cost-effectiveand large-scale synthesis thanks to the short process, the easy reactionand purification.

BEST MODE FOR CARRYING OUT THE INVENTION

To achieve the above objective, the present invention provides thesynthetic process of compound (1) comprising 4 steps; protection,activation and inversion of 3- and 4-OH groups of 2-deoxy-D-ribose, anddeprotection.

The present invention provides the synthetic process of compound (1)comprising the steps of; (A) protection step in which aldehyde group of2-deoxy-D-ribose is protected in the form of acetal.2-deoxy-1-O-alkyl-D-ribopyranoside is prepared by the reaction of2-deoxy-D-ribose with alcohol in the presence of acid; (3) activationstep in which 3- and 4-OH groups of 2-deoxy-D-ribose are activated.2-deoxy-1-O-alkyl-3,4-di-(alkanesulfonyl)-D-ribose or2-deoxy-1-O-alkyl-3,4-di-(arylsulfonyl)-D-ribose is prepared by reactionof the above 2-deoxy-1-O-alkyl-D-ribose with organic sulfonylhalide foractivation of 3- and 4-OH; (C) inversion step in which stereochemistryof 3- and 4-OH groups is changed. Reaction of the above2-deoxy-1-O-alkyl-3,4-di-(alkanesulfonyl)-D-ribose or2-deoxy-1-O-alkyl-3,4-di-(arylsulfonyl)-D-ribose with a metal salt oforganic acid leads to 2-deoxy-L-ribose derivatives of whichstereochemistry of 3- and 4-OH is different from the corresponding2-deoxy-D-ribose derivatives; (D) deprotection step in which2-deoxy-L-ribose is prepared by consecutive reactions of the step (C)products with acid and base.

Each step will be explained in the following.

(1) Protection

In this step, protecting group is introduced in the form of acetal bythe reaction of compound (2), 2-deoxy-D-ribose with alcohol in thepresence of acid.

Here, R1 represents a lower alkyl having 1-5 of carbon number, a benzylor a substituted benzyl. The acid used in this step contains inorganicacid such as hydrochloric acid and sulfuric acid or organic acid such asmethanesulfonic acid and p-toluenesulfonic acid and the concentration ofacid is preferably 1˜10%. A lower alcohol such as methyl alcohol, ethylalcohol, propyl alcohol and butyl alcohol, benzyl alcohol or substitutedbenzyl alcohol may be used.

(2) Activation of 3- and 4-OH Groups: Preparation of2-Deoxy-1-O-alkyl-3,4-di-(alkanesulfonyl)-D-ribose or2-deoxy-1-O-alkyl-3,4-di-(arylsulfonyl)-D-ribose

In this step, compound (4),2-deoxy-1-O-alkyl-3,4-dialaanesulfonyl)-D-ribose or2-deoxy-1-O-alkyl-3,4-di-(arylsulfonyl)-D-ribose is obtained byconverting 3- and 4-OH groups of compound (3) into 3- and 4-sulfonylgroups by the action of organic sulfonyl halide and an organic base. Thepurpose of this reaction is the activation of 3- and 4-OH groups forfurther reaction.

An organic sulfonyl halide used in this step may include a loweralkanesulfonyl halide such as methanesulfonyl chloride andtrifluoromethylsulfonyl chloride and arylsulfonyl halide such asbezenesulfonyl chloride and p-toluenesulfonylchloride. Detailed reactioncondition is accordance with basic methods of organic synthesis.

Here, R1 represents a lower alkyl having 1-8 of carbon number, asubstituted or unsubstituted benzyl and R2 represents a loweralkylsulfonyl having 1-8 of carbon number, a substituted orunsubstituted aryl sulfonyl group.

(3) Inversion (Conversion to L-sugar from D-sugar): Preparation of theMixture of 2-deoxy-1-O-alkyl-3-acyl-L-ribose and2-deoxy-1-O-alkyl-4-acyl-L-ribose

Compound (5), the mixture of 2-deoxy-1-O-alkyl-3-acyl-L-ribose and2-deoxy-1-O-alkyl-4-benzoyl-L-robose in which the stereochemistry of 3-and 4 carbon is changed is prepared through the reaction of compound (4)with a metal salt of organic acid.

A metal salt of organic acid used in this step may include a metal saltof lower alkyl organic acid such as sodium acetate, potassium acetate ora metal salt of aryl organic acid such as sodium benzoate or potassiumbenzoate. A solvent used in this step may include water and organicsolvent such as dimethylformamide (DMF), dimethylacetaride (DMAC), andalohols, but DMF or the mixture of water and organic solvent ispreferable in view of solubility of the reactants.

Here, R1 represents a lower alkyl having 1-8 of carbon number, asubstituted or unsubstituted benzyl and R2 represents a loweralkylsulfonyl having 1-8 of carbon number, a substituted orunsubstituted aryl sulfonyl group.

(4) Deprotection

Compound (1), 2-deoxy-L-ribose is obtained by the stepwise reactions ofcompound (5) with acid and base. Acid and base used in deprotectionconventionally may also be used in this step. The order of the stepwisereactions may be changed according to its convenience.

Compound (1) can be used as a raw material for the further reactionwithout purification or can be purified by the formation of anilidederivative well known as a purification method of 2-deoxy-D-ribose toobtain as solid.

The above preparation method is depicted in the following scheme:

-   -   [R1: lower alkyl having 1-8 of carbon number or substituted or        unsubstituted benzyl    -   R2: lower alkylsulfonyl having 1-8 of carbon number or        substituted or unsubstituted arylsulfonyl    -   R3: lower alkyl having 1-8 of carbon number or substituted or        unsubstituted benzyl]

The syntheses described above provide simple preparation method ofcompound (1) utilizing chief and commercially available reagents withouttoxic reagent such as heavy metal and easily attainable temperature andpressure range.

In addition, separation and purification is easy without specialequipment because the key intermediate and final product can be purifiedby recrystallization.

The raw material, 2-deoxy-D-ribose is not only abundant in naturalproducts, but also obtained by chemical synthesis. All the above reasonmake the procedure mass-producible effectively.

To assist in understanding the present invention more clearly, thefollowing embodiments are appended. The embodiments should not, ofcourse, be construed to limit or alter the scope of the presentinvention. Further, the variations or modifications of the presentinvention which do not depart from the spirit of the present inventioncan easily be made by one of ordinary skill in the art and areconsidered to fall within the scope of the present invention.

PREFERRED EMBODIMENTS Embodiment 1

Protection: Preparation of 2-deoxy-1-O-butyl-D-ribose

To a cooled butyl alcohol containing 3% HCl (56.4 mL) was added2-deoxy-D-robse (10 g) and stirred under −2° C. for 16 hours. Thereaction mixture was neutralized with triethylamine keeping thetemperature under 10° C. and stirred at 20˜25° C. The mixture wasfiltered and washed with acetone (20 mL). The combined filterate andwashing solution was concentrated and used for further reaction withoutpurification.

Embodiment 2

Activation of 3- and 4-OH Groups: Preparation of2-Deoxy-1-O-butyl-3,4-di-(p-toluenesulfonyl)-D-ribose

To the solid of 2-deoxy-1-O-butyl-D-ribose obtained in Embodiment 1 wereadded pyridine (36 mL), p-toluenesulfonyl chloride (42.6 g) stepwiseunder 30° C. and the mixture was stirred at 27˜30° C. for 20 hours. Thereaction mixture was heated to 75±2° C. and stirred for 2 hours. Afterthe completion of reaction, the mixture was cooled to 15˜20° C. andpurified water (30 mL) was added and the resulting mixture was extractedtwice with ethyl acetate (30 mL). The extract was concentrated and ethylalcohol and isopropyl alcohol were added. The solution was cooled,filtered, and dried, to obtain the solid of2-deoxy-1-O-butyl-3,4-di-(p-toluenesulfonyl)-D-ribose (23 g).

Embodiment 3

Conversion to Inform Sugar from D-Form Sugar: Preparation of2-deoxy-1-O-butyl-3-benzoyl-L-ribose and2-deoxy-1-O-butyl-4-benzoyl-L-ribose

To the compound obtained in Embodiment 2 (20 g) were added n-butanol (7mL), water (4.4 mL), N,N-dimethylformamide (27.6 mL) and potassiumbenzoate (21.2 g) and the mixture was heated to 115° C. and reacted for8 hours. After the concentration of the reaction mixture, water andethyl acetate were added to separate organic and water layers. After theorganic layer was concentrated, the residue was mixed with water andevaporated again to concentrate N,N-dimethylformamide efficiently. Theresidue was used for the next reaction.

Embodiment 4

Deprotection: Preparation of 2-deoxy-L-ribose

To the residue obtained in Embodiment 3 were added water (10 mL) and 40%sodium hydroxide solution (10 mL) and the mixture was stirred for 3hours at room temperature. 6N hydrochloric acid (50 mL) was added to thereaction mixture and the resulting mixture was stirred for 4 hours at25˜30° C. to give 2-deoxy-L-ribose. Through the formation of anilidederivative which was already known for its enatiomer 2-deoxy-D-ribose,pure 2-deoxy-L-ribose was obtained as solid (3.4 g).

INDUSTRIAL APPLICABILITY

The present invention is related to the synthetic method for2-deoxy-L-ribose in which reaction and purification is easy at easilyattainable range of temperature and pressure, and of which reagents aremore cheap and less toxic. Additionally, this invention provides moreeconomic method than the previously known process in terms of the costsfor equipments, law-materials, and processing by using the low-cost andnon-toxic reagents starting from 2-deoxy-D-ribose which is naturallyabundant as well as can be synthesized from D-glucose easily.

1. A method for producing 2-deoxy-L-ribose comprising the steps of (A)protection step for preparation of 2-deoxy-1-O-alkyl-D-ribopyranoside,of which the aldehyde group in 2-deoxy-D-ribose is protected in the formof acetal, by reacting 2-deoxy-D-ribose with an alcohol in the presenceof an acid; (B) activation step for preparation of2-deoxy-1-O-alkyl-3,4-di-(alkanesulfonyl)-D-ribose or2-deoxy-1-O-alkyl-3,4-di-(arylsulfonyl)-D-ribose, of which the 3- and4-OH groups in 2-deoxy-D-ribose are activated, by reacting the above2-deoxy-1-O-alkyl-D-ribose and an organic sulfonyl halide in thepresence of a base; (C) inversion step for preparation of a mixture of2-deoxy-1-O-alkyl-3-acyl-L-ribose and 2-deoxy-1-O-alkyl-4-acyl-L-ribose,in which the stereochemistry of 3-OH and 4-OH groups are inverted, byreacting the above 2-deoxy-1-O-alkyl-3,4-di-(alkanesulfonyl)-D-ribose or2-deoxy-1-O-alkyl-3,4-di-(arylsulfonyl)-D-ribose with a metal salt oforganic acid; and (D) deprotection step for preparation for2-deoxy-L-ribose by reactions of the above mixture of2-deoxy-1-O-alkyl-3-acyl-L-ribose and 2-deoxy-1-O-alkyl-4-acyl-L-ribosewith an acid and then with a base, or with a base and then with an acid.2. The method for producing 2-deoxy-L-ribose according to claim 1,wherein the alcohol used in said protection step is a lower aliphaticalcohol having 1-4 of carbon number or benzyl alcohol.
 3. The method forproducing 2-deoxy-L-ribose according to claim 1, wherein the organicsulfonyl halide used in said activation step is a lower alkanesulfonylhalide selected from the group consisting of methane sulfonyl chlorideand trifluoro methane sulfonyl chloride, or an arylsulfonyl halideselected from the group consisting of benzenesulfonyl chloride andp-toluenesulfonyl chloride.
 4. The method for producing 2-deoxy-L-riboseaccording to claim 1, wherein the metal salt of organic acid used insaid conversion step is a metal salt of lower alkyl organic acid having1-8 of carbon number or a metal salt of aryl organic acid.